Heterocyclic compounds for the treatment of pain and use thereof

ABSTRACT

Polycyclic alkaloids of formula (I), ##STR1## wherein R 1  is H, C 1-6  alkyl, or C 6-12  aryl optionally substituted with polar groups; R 2  and R 3  are independently H, OH, C 1-6  alkyl, --C(NH)--NH 2 , a positively charged group, or C 7-13  aralkyl optionally substituted with NH 2 , OH, C 1-6  alkyl, or halogen; or R 2  and R 3  together form a 5 to 6 member ring optionally incorporating a heteroatom; R 4  is H, C 1-6  alkyl, OR 6 , SR 6  or N(R 6 ) 2 , wherein each R 6  is independently H, C 1-3  alkyl; X is O, S, SO, SO 2 , N--R 5 , or C--(R 5 ) 2 , wherein each R 5  is independently H, C 1-6  alkyl, or C 7-13  aralkyl optionally interrupted with one or more heteroatom; n is an integer from 0 to 2; m is an integer from 0 to 3; with the proviso that when X is CH 2  then R1 is not CH 3 , R 2  and R 3  are not both H, R 4  is not OH, m is not 3 and n is not 0. For the treatment of pain and pharmaceutically acceptable compositions comprising those compounds. The compounds of this invention acts as agonists at the opiate receptor.

FIELD OF THE INVENTION

The present invention relates to novel polycyclic opioid receptoragonists having analgesic activity and pharmaceutical acceptablecompositions thereof. In another aspect, the invention relates tomethods and uses relating to the novel agonists and compositions.

BACKGROUND OF THE INVENTION

Narcotic opiate analgesics remain the mainstay of presently availabledrug regimens used to alleviate moderate to severe pain. Opiateanalgesics produce a characteristic antinociceptive response in variousanimal species (including homo sapiens) through activation of specificreceptors in the central nervous system. It is well established thatactivation of one or more of these receptors produces antinociceptiveeffects in relevant animal models of pain assessment.

Multiple types of opioid receptors have been shown to co-exist in higheranimals, of which at least three distinct classes have beencharacterized, with evidence for additional classes or subclasses: mu(μ), kappa (K) and delta (δ). For example, see W. Martin et al., J.Pharmacol. Exp. Ther., 197, p. 517(1975); and J. Lord et al., Nature(London), 257, p. 495 (1977). The μ receptor is located in the brain andappears to be involved in the analgesic effect of morphine-like drugs.κ-Receptor activation in the brain and spinal cord appears capable ofproducing analgesia, particularly at the spinal level. The δ-receptor isfound in some peripheral tissues in addition to the brain and spinalcord, and shows a differentiating affinity for endogenous opioidpeptides known as enkephalins. Finally, although it is doubtful thatσ-receptors are strictly "opioid" in character as they are activated bynon-opioid compounds, the majority of psychotomimetic effects of opioiddrugs, such as dysphoria and hallucinations, appear to be mediated bythis class of receptors.

SUMMARY Of THE INVENTION

The present invention provides for compounds having analgesic activitywhich are novel polycyclic opioid receptor agonists having the generalstructure represented by formula I. ##STR2## wherein R₁ is H, C₁₋₆alkyl, or C₆₋₁₂ aryl optionally substituted with polar groups;

R₂ and R₃ are independently H, OH, C₁₋₆ alkyl, --C(NH)--NH₂, apositively charged group or C₇₋₁₃ aralkyl optionally substituted withNH₂, OH, C₁₋₆ alkyl, or halogen; or R₂ and R₃ together form a 5 to 6member ring optionally incorporating a heteroatom;

R₄ is H, C₁₋₆ alkyl, OR₆, SR₆ or N(R₆)₂, wherein each R₆ isindependently H, C₁₋₃ alkyl, or halogen;

X is O, S, SO, SO₂, or N--R₅, wherein each R₅ is independently H, C₁₋₆alkyl, or C₇₋₁₃ aralkyl optionally interrupted with one or moreheteroatom;

n is an integer from 0 to 2;

m is an integer frcm 0 to 3.

In another aspect of the present invention, there is provided a methodof agonizing opioid receptors in a mammal comprising administering tosaid mammal an opioid receptor agonizing amount of a compound accordingto formula (I).

In a further aspect there is provide a method of inducing analgesia in amammal comprising administering to said mammal a pharmaceuticallyeffective amount of a compound according to formula (I).

It will be appreciated by those skilled in the art that the compounds offormula (I), depending on the substituents, may contain one or morechiral centers and thus exist in the form of many different isomers,optical isomers (i.e. enantiomers) and mixtures thereof includingracemic mixtures. All such isomers, enantiomers and mixtures thereofincluding racemic mixtures are included within the scope of theinvention.

The invention also provides for pharmaceutically acceptable compositionscomprising compounds of formula (I), for use in the management of pain.

The invention also provides for pharmaceutically acceptable compositionscomprising compounds of formula (I), for use as diagnostic aids and/orresearch tools such as radioligands, radiotracers with Positron EmissionTomography or paramagnetic agents for use with Magnetic ResonanceImaging for opiate receptor mediated processes.

The invention further provides the use of a compound of Formula (I) forthe manufacture of therapeutic agents for the management of pain.

The invention further provides the use of a compound of Formula (I) forthe manufacture of chemical compounds for use as diagnostic aids and/orresearch tools such as radioligands, radiotracers with Positron EmissionTomography or paramagnetic agents for use with Magnetic ResonanceImaging for opiate receptor mediated processes.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 indicates dose dependent inhibition of the latency response toradiant heat by compound #9 administered subcutaneously to mice.

FIG. 2 shows dose dependent inhibition of the writhing response (PBQ) bycompound #9 administered orally to mice.

FIG. 3 depicts dose dependent inhibition of the writhing response (PBQ)by compound #9 administered subcutaneously to mice.

DETAILED DESCRIPTION OF THE INVENTION

The following common abbreviations are used throughout the specificationand in the claims:

The term "ED₅₀ " as shown in Table 1 for the PBQ writhing assay isdefined as the dose of drug which induces a 50% reduction in the numberof writhes observed compared to the control.

The term a "ED₅₀ " used in the hot-plate assay (FIG. 1) is defined asthe dose of drug required to increase the latency of response 2-foldcompared to controls and was determined by log-probit analysis.

The term "K_(i) " is the binding inhibition constant. The term"K_(i).sup.δ /K_(i).sup.μ " is a value that may be used to measureselectivity. This ratio represents the relationship of the affinities ofcompounds for binding to the μ- and δ-receptors.

As used in this application, the term `alkyl` represents a saturated orunsaturated, substituted (by a halogen, hydroxyl, amino, or C₆₋₂₀ aryl)or unsubstituted; straight chain, branched chain, or cyclic hydrocarbonmoiety wherein said straight chain, branched chain, or cyclichydrocarbon moiety can be interrupted by one or more heteroatoms (suchas oxygen, nitrogen or sulfur).

The term "heteroatom" as used hereinafter represents N, O and S as wellas SO and SO₂.

The term `aryl` represents a carbocyclic moiety which may be substituted(e.g. C₁₋₆ alkyl, halogen, hydroxyl, amino), interrupted by at least oneheteroatom (e.g., N, O or S) and containing at least one benzenoid-typering (e.g. phenyl and naphthyl).

The term `aralkyl` represents an aryl group attached to the adjacentatom by an alkyl (e.g. benzyl).

The compounds of the present invention are represented by Formula (I) asdefined above.

Preferably, R₁ is cyclohexyl.

Preferably, R₁ is phenyl optionally substituted with polar groups.

Preferred polar groups are COOH, NH₂ or guanidine.

More preferably, R₁ is H.

Most preferably, R₁ is CH₃.

Preferably, R₂ is H.

Preferably, R₃ is OH.

Most preferably, R₃ is H.

Preferably, R₄ is OCH₃.

Preferably, R₄ is OH.

Preferably, X is NH.

More preferably, X is O.

Most preferably, X is S.

Preferably, R₅ is C₁₋₆ alkyl.

More preferably, R₅ is CH₃.

Most preferably, R₅ is H.

Preferably, n is 0.

Preferably, m is 3.

A preferred compound of the invention includes:

Compound #8b:5,6,7,8,9,11,12-heptahydro-3-methoxy-5-methyl-10-thia-5,11-methanobenzocyclodecene-13-amine.

A preferred compound of the invention includes:

Compound #9:5,6,7,8,9,11,12-heptahydro-3-hydroxy-5-methyl-10-thia-5,11-methanobenzocyclodecen-13-amine(sulphazocine).

A preferred compound of the invention includes:

Compound #10:5,6,7,8,9,11,12-heptahydro-3-hydroxy-5-methyl-10-thia-5,11-methanobenzocyclodecene-13-hydroxylamine.

A preferred compound of the invention includes:

Compound #9a(-)-trans-5,6,7,8,9,11,12-heptahydro-10-thia-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13-amine;

A preferred compound of the invention includes:

Compound #11trans-5,6,7,8,9,11,12-heptahydro-10-thia-3-hydroxy-5-methyl-5,11l-methanobenzocyclodecen-13-guanidine

A preferred compound of the invention includes:

Compound #12trans-5,6,7,8,9,11,12-heptahydro-10-sulphono-3-hydroxy-5-methyl-5,11-methanobenzocyclo-decen-13-amine

More preferred compounds of the invention include:

Compound #9: 5,6,7,8,9,11,12-heptahydro-3-hydroxy-5-methyl-10-thia-5,11methanobenzocyclodecen-13-amine (sulphazocine); and

compound #10:5,6,7,8,9,11,12-heptahydro-3-hydroxy-5-methyl-10-thia-5,11-methanobenzocyclodecene-13-hydroxylamine;

Most preferred compound of the invention include:

Compound #9:5,6,7,8,9,11,12-heptahydro-3-hydroxy-5-methyl-10-thia-5,11-methanobenzocyclodecen-13-amine(sulphazocine); and

compound #9a(-)-trans-5,6,7,8,9,11,12-heptahydro-10-thia-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13-amine.

The preferred compounds of the present invention can be synthesizedusing conventional preparative steps and recovery methods known to thoseskilled in the art of organic and bio-organic synthesis, while providingnew and unique combinations for the overall synthesis of each compound.Preferred synthetic routes for intermediates involved in the synthesisas well as the resulting compounds of the present invention follow.Successful preparation of these compounds is possible by way of severalsynthetic routes one of which is outlined in Scheme 1. ##STR3##

The steps illustrated in Scheme 1 can be briefly described as follows:

Step 1:

Compound I, an alkyl-1-tetralone, is treated with an appropriateGrignard Reagent such as methyl magnesium bromide in a dry non-polarsolvent such as THF, to generate the tertiary alcohol, Compound II.

Step 2:

The alcohol, Compound II is dehydrated under acidic conditions, such asaqueous saturated NH₄ Cl, to yield Compound III.

Step 3:

The double bond at position 1 on the olefin is epoxidized using standardreagents and solvents, such monoperoxyphthalic acid magnesium salt inisopropanol, to produce the epoxide, Compound IV.

Step 4:

The epoxide is rearranged under acidic conditions, such as aqueousNaHCO₃, using standard techniques to generate the ketone, Compound V.

Step 5:

Alkylation of the bis-alkyl-2-tetrone (Compound V) is accomplished underbasic conditions in non-polar solvent using a dihaloalkyl reagent, suchas dibromobutane, to yield Compound VI.

Step 6:

Nucleophilic displacement of bromide is accomplished with an appropriateacylating agent, such as potassium thiacetate to produce Compound VII.

Step 7:

The 3 position of the acylated tetralone (Compound VII) is halogenatedin a non-polar solvent, such as a mixture of benzene and dry THF, usingan appropriate reagent and non-polar solvent such as Bromine in dry THFto generate Compound VIII.

Step 8:

The side chain is cyclized under basic conditions using standardreagents and solvents such as lithium bromide and dry THF under Argon,with the addition of a base such as sodium methoxide, generating thepolycyclic compound (Compound IX).

Step 9:

The ketone group of compound IX is converted to an alkyloxime usingstandard procedures well known in the art affording compound X.

Steps 10 and 11:

Compound X is reduced using a Borane-THF complex. If conducted in THF, a50:50 mixture of compounds XI and XII is obtained. If the reaction isconducted in diglyme (2-methoxyethyl ether), the amine, (Compound XII)is selectively produced.

Step 12:

Compound XI can be recycled and reduced to the amine using a Borane-THFcomplex conducted in diglyme to yield Compound XII.

It is also appreciated that the compounds of the present invention canbe modified by one skilled in the art in such a manner as to attachlabels such as radioactive labels enabling detection of the compound foruse as a radiotracer. The compounds of the present invention may be usedas agonists at the opiate receptor in vitro or ex vivo as in the case ofradio-labeling agents, radiotracers for use with Positron EmissionTomography, paramagnetic agents for use in Magnetic Resonance Imaging,and NMDA receptor-linked calcium channel antagonists.

It is appreciated that the compounds of the present invention can bemodified by one skilled in the art in such a manner as to prevent accessinto the central nervous system such that they can function as opiatereceptor agonists in peripheral tissues.

The present invention also provides pharmaceutical compositions whichcomprise a pharmaceutically effective amount of the compounds of thisinvention, or pharmaceutically acceptable salts thereof, and,preferably, a pharmaceutically acceptable carrier or adjuvant. The term"pharmaceutically effective amount" is the amount of compound requiredupon administration to a mammal in order to induce analgesia. Also, theterm "opioid receptor agonizing amount" refers to the amount of compoundadministered to a mammal necessary to bind and/or activate opioidreceptors in vivo.

Therapeutic methods of this invention comprise the step of treatingpatients in a pharmaceutically acceptable manner with those compounds orcompositions. Such compositions may be in the form of tablets, capsules,caplets, powders, granules, lozenges, suppositories, reconstitutablepowders, or liquid preparations, such as oral or sterile parenteralsolutions or suspensions.

The therapeutic agents of the present invention may be administeredalone or in combination with pharmaceutically acceptable carriers. Theproportion of each carrier is determined by the solubility and chemicalnature of the compound, the route of administration, and standardpharmaceutical practice.

In order to obtain consistency of administration, it is preferred that acomposition of the invention is in the form of a unit dose. The unitdose presentation forms for oral administration may be tablets andcapsules and may contain conventional excipients. For example, bindingagents, such as acacia, gelatin, sorbitol, or polyvinylpyrolidone;fillers, such as lactose, sugar, maize-starch, calcium phosphate,sorbitol or glycine; tabletting lubricants such as magnesium stearate;disintegrants, such as starch, polyvinylpyrrolidone, sodium starchglycollate or microcrystalline cellulose; or pharmaceutically acceptablewetting agents such as sodium lauryl sulphate.

The compounds may be injected parenterally; this being intramuscularly,intravenously, or subcutaneously. For parenteral administration, thecompound may be used in the form of sterile solutions containing othersolutes, for example, sufficient saline or glucose to make the solutionisotonic.

The compounds may be administered orally in the form of tablets,capsules, or granules containing suitable excipients such as starch,lactose, white sugar and the like. The compounds may be administeredorally in the form of solutions which may contain coloring and/orflavoring agents. The compounds may also be administered sublingually inthe form of tracheas or lozenges in which each active ingredient ismixed with sugar or corn syrups, flavoring agents and dyes, and thendehydrated sufficiently to make the mixture suitable for pressing intosolid form.

The solid oral compositions may be prepared by conventional methods ofblending, filling, tabletting, or the like. Repeated blending operationsmay be used to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are, of course,conventional in the art. The tablets may be coated according to methodswell known in normal pharmaceutical practice, in particular with anenteric coating.

Oral liquid preparations may be in the form of emulsions, syrups, orelixirs, or may be presented as a dry product for reconstitution withwater or other suitable vehicle before use. Such liquid preparations mayor may not contain conventional additives. For example suspendingagents, such as sorbitol, syrup, methyl cellulose, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, orhydrogenated edible fats; emulsifying agents, such as sorbitanmonooleate or acaci; non-aqueous vehicles (which may include edibleoils), such as almond oil, fractionated coconut oil, oily estersselected from the group consisting of glycerine, propylene glycol,ethylene glycol, and ethyl alcohol; preservatives, for instance methylpara-hydroxybenzoate, ethyl para-hydroxybenzoate, n-propylparahydroxybenzoate, or n-butyl parahydroxybenzoate of sorbic acid; and,if desired, conventional flavoring or coloring agents.

For parenteral administration, fluid unit dosage forms may be preparedby utilizing the compound and a sterile vehicle, and, depending on theconcentration employed, may be either suspended or dissolved in thevehicle. Once in solution, the compound may be injected and filtersterilized before filling a suitable vial or ampoule and subsequentlysealing the carrier or storage package. Adjuvants, such as a localanesthetic, a preservative or a buffering agent, may be dissolved in thevehicle prior to use. Stability of the pharmaceutical composition may beenhanced by freezing the composition after filling the vial and removingthe water under vacuum, (e.g., freeze drying the composition).Parenteral suspensions may be prepared in substantially the same manner,except that the compound should be suspended in the vehicle rather thanbeing dissolved, and, further, sterilization is not achievable byfiltration. The compound may be sterilized, however, by exposing it toethylene oxide before suspending it in the sterile vehicle. A surfactantor wetting solution may be advantageously included in the composition tofacilitate uniform distribution of the compound.

The pharmaceutical compositions of this invention comprise apharmaceutically effective amount of a compound of this invention and apharmaceutically acceptable carrier.

Typically, they contain from about 0.1% to about 99% by weight,preferably from about 10% to about 60% by weight, of a compound of thisinvention, depending on which method of administration is employed.

The present invention also provides a method for management of pain inpatients, such as mammals, including humans, which comprises the step ofadministering to the patient a pharmaceutically effective amount of acompound, a pharmaceutically acceptable salt thereof, or apharmaceutical composition as described above.

Physicians will determine the dosage of the present therapeutic agentswhich will be most suitable. Dosages may vary with the mode ofadministration and the particular compound chosen. In addition, thedosage may vary with the particular patient under treatment. The dosageof the compound used in the treatment will vary, depending on theseriousness of the disorder, the weight of the patient, the relativeefficacy of the compound and the judgment of the treating physician.Such therapy may extend for several weeks, in an intermittent oruninterrupted manner, until the patient's symptoms are eliminated.

A number of heterocyclic compounds based on the general formula I, havebeen prepared and evaluated as opioid receptor agonists. These compoundsare listed in Table 1 along with their respective binding inhibitionconstants and inhibitory activity in the PBQ assay. These resultsindicate that the compounds of the invention are effective as analgesicagents.

The compounds of the present invention may be used as opiate receptoragonists in vitro or ex vivo as in the case of, for example,radio-labeling agents, radiotracers, paramagnetic agents. The compoundsof the invention may be used as research tools and/or diagnostic aids.

For preparation of the compounds of this invention, various methods canbe employed depending upon the particular starting materials and/orintermediates involved. Successful preparation of these compounds ispossible by way of several synthetic routes some of which are outlinedbelow.

To further assist in understanding the present invention, the followingnon-limiting examples of such opiate receptor agonist compounds areprovided. The following examples, of course, should not be construed asspecifically limiting the present invention, variations presently knownor later developed, which would be within the purview of one skilled inthe art and considered to fall within the scope of the present inventionas described herein.

EXAMPLE 1 Preparation of 1,2-dihydro-7-methoxy-4-methylnaphthalene##STR4##

7-methoxy-1-tetralone (25 g) was dried via azeotropic distillation oftoluene and dissolved in dried THF (200 ml). The solution was cooled at-70° C. (under Ar and methyl magnesium bromide (1.4 M in toluene/THF,187.5 ml) was added. The combined reaction mixture was allowed to stirat ambient temperature overnight. It was carefully treated with aqueoussaturated NH₄ Cl and extracted with ethylacetate. The latter solutionwas washed with brine, dried over MgSO₄ and evaporated. The residue wasdissolved in benzene (150 ml), p-TSOH (0.1 g) was added and the mixturewas heated to reflux using a Dean-Stark condenser until the dehydrationreaction was complete. This benzene solution was diluted withethylacetate, washed with NaHCO₃, dried over MgSO₄ and evaporated. Theresidue was extracted with hexanes, passed through a silica gel columnand eluted with a mixture of hexanes and ethylacetate (1:0, 400:1,200:1). The yield of the product was 20.87 g (84.42%).

¹ H NMR (300 MHz, CDCl₃) δ: 2.05 (s, 3H); 2.23 (m, 2H); 2.69 (t, 2H);3.81 (s, 3H) 5.88 (m, 1H); 6.68-7.06 (m, 3H) ppm.

EXAMPLE 2 Preparation of 7-methoxy-1-methyl-2-tetralone ##STR5##

Dihydro-7-methoxy-4-methylnaphthalene (20.87 g) was dissolved inisopropanol (100 ml) and cooled in an ice bath. Monoperoxyphthalic acidmagnesium salt (mmpp) (17 g) was added, then water (50 ml) was added andthe mixture was stirred at room temperature for 2 hours. When oxidationwas complete, the product mixture was hydrolyzed with aqueous NaHCO₃,partially evaporated and extracted with ethylacetate. The latter extractwas washed with brine and evaporated. The residue was dissolved in amixture of ethanol (156 ml), water (121 ml) and conc. H₂ SO₄ (24.3 ml),and heated to reflux under N₂ atmosphere for 3 hours, cooled andneutralized with NaHCO₃. After partial evaporation, the residue wasextracted with ethylacetate, washed with brine, dried over MgSO₄ andevaporated. The product was purified on a silica gel column using amixture of hexanes and ethylacetate (100:1, 50:1, 50:1.5). The yield ofthe product was 16.2 g (71%).

¹ H NMR (300 MHz, CDCl₃) δ: 1.47 (d, 3H); 2.55 (m, 2H); 3.02 (m, 2H);3.5 (m, 1H); 3.81 (s, 3H); 6.75-6.77 (m, 3H) ppm. IR (film) 1714 cm⁻¹.

EXAMPLE 3 Preparation of1-(4'-bromobutyl)-1-methyl-7-methoxy-2-tetralone ##STR6##

7-Methoxy-1-methyl-2-tetralone (4 g) was dried via azeotropicdistillation of toluene, dissolved in dry THF (150 ml), cooled in an icebath under Ar atmosphere and sodium bis (trimethylsilyl) amide solution(NaHMDS)(1 M in THF, 23.13 ml) was added and stirred for 1/2 hour.1,4-Dibromobutane (9.78 ml) was added and the reaction mixture wasallowed to warm up to room temperature overnight, after which it washydrolyzed with brine, extracted with ethylacetate, dried over MgSO₄ andevaporated. The product mixture was purified on a silica gel columnusing a mixture of hexanes and ethylacetate (200:1, 150:1,100:1, 75:1and 50:1). The yield of the product was 5.19 g (76%).

¹ H NMR: (300 MHz, CDCl₃) δ: 1.09 (m, 2H); 1.37 (s, 3H) 1.71 (m, 3H);2.1 (m, 3H); 2.68 (m, 2H); 2.97 (m, 2H); 3.26 (t, 2H); 3.8 (s, 3H),6.72-7.09 (m, 3H) ppm.

EXAMPLE 4 Preparation of1-(4'-acetothiobutyl)-1-methyl-7-methoxy-2-tetralone ##STR7##

1-(4'-Bromobutyl)-1-methyl-7-methoxy-2-tetralone (4.48 g) was dried viaazeotropic distillation of toluene and dissolved in dry DMF (25 ml).Potassium thiacetate (5.86 g) was added and the mixture was allowed tostir under Ar atmosphere overnight, after which it was extracted withethylacetate, washed with brine, dried over MgSO₄ and evaporated. Theresidue was purified on a silica gel column using a mixture of hexanesand ethylacetate (75:1, 50:1, 20:1). The yield of the product was 3.9 g(88.3%).

¹ H NMR (300 MHz, CDCl₃) δ: 0.99 (m, 2H); 1.5 (m, 6H); 2.07 (m, 1H);2.25 (s, 3H); 2.65 (m, 4H); 2.95 (m, 2H); 3.79 (s, 3H); 6.71-7.08 (m,3H) ppm.

EXAMPLE 5 Preparation of an epimeric mixture of3-bromo-1-(4'-acetothiobutyl)-1-methyl-7-methoxy-2-tetralone ##STR8##

1-(4'-Acetothiobutyl)-1-methyl-7-methoxy-2-tetralone (4 g) was dried viaazeotropic distillation of toluene. It was dissolved in a mixture ofbenzene (244 ml) and dry THF (64 ml) and stirred at room temperatureunder Ar atmosphere. Bromine (0.8 ml) was dissolved in dry THF (26 ml)and gradually added to the reaction mixture under Ar flow. After 1 hourof stirring, the product mixture was hydrolyzed with aqueous NaHCO₃,extracted with ethylacetate, washed with brine, dried over MgSO₄ andevaporated. The residue was dried via azeotropic distillation of tolueneand then dried further under high vacuum.

EXAMPLE 6 Preparation of 5,6,7,8,9,11,1-heptahydro-3-methoxy-5-methyl-10-thia-5,11-ethanobenzocyclodecen-13-one ##STR9##

An epimeric mixture of3-bromo-1-(4'-acetothiobutyl)-1-methyl-7-methoxy-2-tetralone(approximately 6.25 mmol) was dried via azeotropic distillation oftoluene and dissolved in dry THF (200 ml), Lithium Bromide (dry, 0.54 g)was added, the solution was degassed with Ar at room temperature for onehour, and was cooled in an ice bath, well stirred, with a gentle flow ofAr passing through it. Sodium methoxide (0.5 M in Methanol, 13.75 ml)was dissolved in dry THF (75 ml), degassed with Ar at room temperaturefor one hour, after which it was added to the latter solution through asyringe pump over 4 hours. The combined reaction mixture was stirred foran additional 1/2 hour, diluted with ethylacetate (100 ml), washed withbrine, dried over MgSO₄ and evaporated. The residue was purified on asilica gel column using a mixture of hexanes and ethylacetate (75:1,50:1). The yield of product was approximately 50-55%. It solidified onstanding.

¹ H NMR (300 MHz, CDCl₃) δ: 1.4-1.95 (m, 4H); 2.85 (m, 2H); 2.7-3 (m,2H); 3.4 (m, 1H); 3.82 (m, 4H); 6.7-7.1 (m, 3H) ppm. IR (film) 1693,1609 cm⁻¹.

EXAMPLE 7 Preparation of epimeric 5,6,7,8,9,11,12 heptahydro-3-methoxy-5-methyl-10-thia-5,11-methanobenzocyclodecen-13-oxime##STR10##

5,6,7,8,9,11,12-Heptahydro-3-methoxy-5-methyl-10-thia-5,11-methanobenzocyclodecen-13-one(1.32 g) was dried via azeotropic distillation of toluene, mixed withhydroxyl amine hydrochloride (2.64 g) and dry pyridine (5.2 ml) wasadded. Combined mixture was heated at 80° C. for 2 days. It was cooled,diluted with CH₂ Cl₂ and washed with brine. After drying over MgSO₄, thesolvent was evaporated off and the residue was purified on a silica gelcolumn using a mixture of hexanes and ethylacetate (50:1, 25:1, 10:1,5:1 2:1). The yield of the product was 1.22 g. (92%).

¹ H NMR (300 MHz, CDCl₃) δ; 1.2-1.9 (m, 9H); 2.4 (m, 2H); 2.85 (m, 2H);3.2 (dd, 1H); 3.8 (s, 3H); 5.11 (t, 1H); 6.6-7.1 (m, 3H) ppm. IR (film)1609, 2200, 3250 cm⁻¹ ; Mass Spectrometry: m/z 292.

EXAXPLE 8 Preparation of5,6,7,8,9,11,12-heptahydro-3-methoxy-5-methyl-10-thia-5,11-methanobenzocyclodecen-13-hydroxylamine--Compound #8a and5,6,7,8,9,11,12-heptahydro-3-methoxy-5-methyl-10-thia-5,11-methanobenzocyclodecen-13-amine-compound#8b ##STR11##

5,6,7,8,9,11,12-Heptahydro-3-methoxy-5-methyl-10-thia-5,11-methanobenzocyclodecen-13-oxime(isomeric mixture, 0.3 g) was dried with toluene and dissolved in dryTHF (30 ml). It was cooled in an ice bath under Ar atmosphere.Borane--THF complex (1M solution in THF, 7.87 ml) was added and thecombined mixture was heated to reflux for 30 hours. It was cooled in anice bath. Water (0.4 ml) and concentrated HCl (0.6 ml) were addedcarefully in respective order. The mixture was heated to reflux for 15minutes, cooled and evaporated. The residue was basified withconcentrated NH₄ OH to pH 12, extracted with CH₂ Cl₂, washed with brine,dried over MgSO₄ and evaporated. The residue was purified on a silicagel column using a mixture of hexanes and ethylacetate (50:1, 20:1,10:1, 5:1, 5:1.5, 2:1, 1:1 and 1:2). The yield of5,6,7,8,9,11,12-heptahydro-3-methoxy-5-methyl-10-thia-5,11-methanobenzocyclodecen-13-hydroxylaminewas 0.073 g (23.1%). It was crystallized from a mixture of ethylacetateand hexanes.

¹ H NMR (300 MHz, CDCl₃) δ: 1.1-1.91 (m, 9H); 2.3 (m, 2H); 3.30 (d, 1H);3.37 (m, 2H); 3.7 (m, 1H), 3.78 (s, 3H), 6.6-7.1 (m, 3H) ppm. IR (film):1612, 3300 cm⁻¹ ; Mass Spectrometry: 293.8, 275.8, 260.8.

The structure of #8a was confirmed by single crystal X-raycrystallography.

The yield of5,6,7,8,9,11,12-heptahydro-3-methoxy-5-methyl-10-thia-5,11-methanobenzocyclodecen-13-aminewas 0.0968 g. (32%). The free base was soluble in hexanes.

¹ H NMR (300 MHz, CDCl₃) δ: 0.8-2.5 (m, 11H), 3.18 (m, 3H), 3.6 (q, 1H),3.8 (s, 3H) 6.6-7.1 (m, 3H) ppm.

This product was dissolved in ether (40 ml) and acidified withMethanol-HCl. The suspension was allowed to settle and filtered. Theprecipitate was washed with ether and dried, yielding 0.090 g ofproduct.

¹ H NMR (300 MHz, CDCl₃) δ: 0.8-1.7 (m, 6H); 1.8 (m, 2H); 2.0-2.5 (m,3H); 3.45 (m, 2H); 3.5 (m, 2H); 3.8 (S, 3H) 6.7-7.1 (m, 3H) ppm. MassSpectrometry: m/z 278.

EXAMPLE 9 Preparation of5,6,7,8,9,11,12-heptahydro-3-hydroxy-5-methyl-10-thia-5,11methanobenzocyclodecen-13-amine (sulphazocine) compound #9 ##STR12##

5,6,7,8,9,11,12-Heptahydro-3-methoxy-5-methyl-10-thia-5,11-methanobenzocyclodecen-13-amine(0.260 g) was dried via azeotropic distillation of toluene and dissolvedin dry CH₂ Cl₂ (40 ml). It was cooled at -70° under Ar atmosphere. Borontribromide solution (1M solution in CH₂ Cl₂, 187 ml) was added and thecombined mixture was allowed to stir at ambient temperature overnight.The reaction mixture was hydrolyzed with NaHCO₃, the pH lowered with NH₄OH to 12, and extracted with CH₂ Cl₂. The latter solution was dried overMgSO₄ and evaporated. The residue was purified on a silica gel columnusing a mixture of toluene and ethylacetate. (10:1, 5:1, 2:1, 1:1, 1:2).

The yield of5,6,7,8,9,11,12-heptahydro-3-hydroxy-5-methyl-10-thia-5,11-methanobenzocyclodecen-13-amine was 0.162 g (65%).

¹ H NMR (350 MHz, DMSO-D₆) δ: 1.02 (m, 1H); 1.25 (m, 5H) 1.55 (m 2H);2.01 (m, 2H); 2.55 (m, 1H); 2.97 (d, 1H) 3.08 (m, 1H), 3.14 (m, 2H);6.4-6.9 (m, 3H) ppm.

The above product was converted to its hydrochloride form and purifiedvia HPLC.

EXAMPLE 10 Preparation of 5,6,7,8,9,11,12-heptahydro-3-hydroxy-5-methyl-10-thia-5,11-methanobenzocyclodecen-13-hydroxylaminecompound #10 ##STR13##

5,6,7,8,9,11,12-heptahydro-3-methoxy-5-methyl-10-thia-5,11-methanobenzoxyclodecen-13-hydroxylamine (0.166 g) was dissolved in a mixture of acetic acid (4.5 ml) and48% HBr (4.5 ml). It was cooled, neutralized carefully with NaHCO₃ andextracted with CH₂ Cl₂. Latter solution was washed with brine, driedover MgSO₄ and evaporated. The residue was purified on a silica gelcolumn using a mixture of hexanes and ethylacetate (10:1, 10:1.5, 5:1).The yield of5,6,7,8,9,11,12-heptahydro-3-hydroxy-5-methyl-10-thia-5,11-methanobenzocyclodecen-13-hydroxylaminewas 0.035 g (22%).

¹ H NMR (300 MHz, CDCl₃) δ: 1.1-1.91 (m, 9H); 2.30 (m, 2H); 3.28 (m,1H), 3.34 (m, 2H); 3.7 (m, 1H), 6.6-7.0 (m, 3H) ppm.

Above product was converted to its hydrochloride form and purified byHPLC.

EXAMPLE 11 Preparation of compound #9a(-)-trans-5,6,7,8,9,11,12-heptahydro-10-thia-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13-amine

Compound #9 (2.96 g) was mixed with D-tartaric acid (2.01 g) dissolvedin boiling ethanol (95%, 50 mL) and filtered. The insoluble mass waswashed with hot ethanol (25 mL). Combined filtrates were evaporated todryness and the residue was redissolved in hot ethanol (20 mL). A fluffysolid mass was collected and redissolved in hot ethanol (15 mL).Crystallization was allowed to proceed undisturbed at room temperaturefor 2 days. Semicrystalline mass was further subjected to similarfractional crystallization process two more times. A sample at thisstage was found to have a diasteromeric purity of 98% via chiralderivatization with Marfey's reagent (0,267 g).

The tartrate salt of the title compound (0.1 g) was dissolved in hotmethanol (20 mL) and transferred to a column packed with AmberliteIRA-400 (Cl⁻ form) ion exchange resin (5 g, washed successively withmethanol, water, 0.1M HCl, water and methanol). The column was washedwith methanol (100 mL) and water (100 mL) in succession. Combinedeluents were evaporated off and lyophilized. Residue (0.076 g)

EXAMPLE 12 Preparation of compound #9b(+)-trans-5,6,7,8,9,11,12-heptahydro-10-thia-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13amine

Compound #9-D-tartrate salt (highly enriched in dextrorotatorydiastereomer 1.5 g) was mixed with NH₄ OH (10 mL) saturated with sodiumchloride and extracted with methylene chloride. The latter was washedwith brine, dried over MgSO₄ and evaporated. Residue (1.27 g) was mixedwith L-tartaric acid (0.87 g) and boiled with ethanol (95%, 100 mL)filtered, the filtrate then being allowed to crystallize at roomtemperature for 2 days. The precipitated mass was allowed to crystallizeslowly from hot isopropanol. A sample was found to have a diastereomericpurity of 97% via chiral derivatization with Marfey's reagent to give0.1515 g yield.

The tartrate salt of the title compound (0.076 g) was dissolved in hotmethanol (25 mL) and transferred to a column packed with activatedAmberlite IRA-400 (Cl⁻ form, 5 g) which was then washed with methanol(100 mL) and water (100 mL) successively. Combined filtrates wereevaporated and lyophilized residue (0.058 g)

EXAMPLE 13 Preparation of compound #11trans-5,6,7,8,9,11,12-heptahydro-10-thia-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13-guanidine##STR14##

Compound #9 (0.35 g) was dried via azeotropic distillation with tolueneand dissolved in dry pyridine (5 mL). 1H-pyrazole-1-carboxamidinehydrochloride (1.29 g) and diisopropyl ethylamine (1.74 mL) was added.Combined mixture was heated at 80° C. under nitrogen atmosphere for 4days. Solvent was evaporated off and the residue was purified on asilica gel column using a mixture of methylene chloride and methanol.The product (0.41 g) was dissolved in methanol saturated with hydrogenchloride (5 mL) and the solvent evaporated off. The residue was purifiedby HPLC yielding 0.045 g final product.

EXAMPLE 14 Preparation of compound #12trans-5,6,7,8,9,11,12-heptahydro-10-sulphono-3-hydroxy-5-methyl-5,11-methanobenzocyclo-decen-13-amine##STR15##

Compound #9 (0.1 g) was dried via azeotropic distillation of toluene,dissolved in dry methylene chloride (20 mL) and cooled in an ice bathunder Ar atmosphere. Trifluoroacetic anhydride (0.54 mL) and pyridine(0.5 mL) were added. After stirring at room temperature overnight thereaction mixture was hydrolyzed with aqueous solution of sodiumbicarbonate, extracted with methylene chloride, washed with brine, driedover MgSO₄ and evaporated. Residue was purified on a silica gel columnusing a mixture of hexanes and methylene chloride to yield 0.068 g oftrans-5,6,7,8,9,11,12-heptahydro-10-thia-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13-trifluoroacetamide.

Trans-5,6,7,8,9,11,12-heptahydro-10-thia-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13-trifluoroacetamidewas dissolved in a mixture of ethanol (2 mL) and water (1 mL) and thencooled in an ice bath. Monoperoxyphthalic acid, magnesium salthexahydrate (0.21 g) was added. After 1 hour aqueous saturated sodiumbicarbonate (5 mL) was added. Combined mixture was stirred at roomtemperature overnight and evaporated off and the residue extracted withmethylene chloride. The latter solution was washed with brine andevaporated yielding 0.123 gtrans-5,6,7,8,9,11,12-heptahydro-10-sulphono-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13-trifluoroacetamide.

Trans-5,6,7,8,9,11,12-heptahydro-10-sulphono-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13-trifluoroacetamide(0.123 g) was dried via azeotropic distillation with toluene andanhydrous hydrazine (2 mL) was added. The mixture was stirred at roomtemperature for 2 days then evaporated and dried under vacuum. Theproduct mixture was dissolved in methanol (2 mL) and allowed to stand atroom temperature. Crystalline material (0.0372 g) was filtered out anddissolved in saturated solution of hydrogen chloride in methanol (2 mL)and then evaporated off. The residue was lyophilized yielding 0.031 g ofthe title compound.

ACTIVITY STUDIES:

Antinociceptive activity of compounds of the invention was determined invivo in a PBQ writhing model and in the hot plate test in rodents.Inhibition of PBQ (phenyl-ρ-benzoquinone) induced writhing in mice is anassessment of both central and peripherally-mediated analgesia. Forexperimental protocol see Sigmund et al., Proc. Soc. Ex. Biol. Med., 95,p. 729 (1957) which is incorporated herein by reference.Centrally-mediated analgesia was determined by the inhibition of a hotplate response in mice. For experimental protocol see G. Woolfe and A.Macdonald, J. Pharmacol. Exp. Ther., 80, p. 300 (1994) which isincorporated herein by reference. Assays measuring opioid receptorbinding affinities for μ, δ and κ receptors as well as GPI and MVDassays were determined through experimental protocol set out in Schilleret al., Biophys. Res. Commun., 85, p. 1322 (1975); Rothman et al,Peptides, Vol 11, pp 311-331, 1990; Kaffa et al, Peptides 15(3),401-404, 1994; Fowler et al, Neurochem. Int 24(5), 401-426, 1994; andLeslie F., Pharmacological Review 39(3), 197-249, 1987 incorporatedherein by reference.

EXAMPLE 15 Radio Receptor Binding Assay

A. Membrane Preparation

Male Sprague-Dawley rats weighing between 350-450 g were sacrificed byinhalation of CO₂. The rats were decapitated and the brains minuscerebellum were removed and placed in ice-cold saline solution and thenhomogenized in ice-cold 50 MM Tris buffer pH 7.4 (10 ml/brain). Themembranes were centrifuged at 14000 rpm for 30 min. at 4° C. The pelletswere re-suspended in approximately 6 ml/brain of ice-cold Tris buffer 50mM pH 7.4 and stored at -78° C. until ready for use. Proteinquantification of the brain homogenate was conducted according to theprotein assay kit purchased from Bio-Rad.

B. Radioligand Assay

(³ H)-DAMGO and (³ H) DADLE were used as radioligands for the μ and δreceptors, respectively. Radioligand 50 μl, membranes 100 μl andserially diluted test compound were incubated for 1 hr at 22° C. Nonspecific binding was determined using 500 fold excess of unlabeledligand in the presence of tracer and membranes. Free ligand wasseparated from bound by filtration through Whatman GF/B paper (presoakedin polyethylenimine 1% aqueous solution) and rinsing with ice-cold 50 mMTris pH 7 4 using a Brandel cell harvester. The filters were dried andradioactivity was counted in a 24 well microplate in the presence of 500ml scintillant per well. Radioactivity was measured using a Wallac 1450Microbeta counter.

Displacement curves were drawn using Microsoft Excel program. The Ki'sfor the various compounds were determined from the IC₅₀ according to theCheng and Prusoff equation.

EXAXPLE 16 Phenylquinone Writhing Assay

A. Subjects

The test was performed using CD #1 male mice (Charles River) weighingbetween 19 and 25 g. Animals were maintained in constant conditions oflight, temperature and humidity. The animals were acclimatized for threedays prior to experimentation.

B. Drug Preparation and Dosage Procedure

A solution of phenylquinone (0.02%) was prepared in the followingfashion. 20 mg of phenylquinone was dissolved in 5 ml ethanol 90%. Thephenylquinone solution was slowly added to 95 ml of distilled water withcontinuous stirring and gentle heating. The phenylquinone solution wasprotected from light at all times and a new solution was prepared everyday for the test. It is recommended to wait 2 hours before using thephenylquinone solution.

All test compounds were dissolved in distilled water and administeredsubcutaneously or by oral gavage.

Mice were injected, by intraperitoneal route, with a solution of 0.02%phenylquinone (2-phenyl-1,4-benzoquinone, Sigma). The phenylquinone wasinjected at various time intervals of 20, 60, 120 and 180 minutes afteradministration of the compound (or vehicle, or standard).

EXAMPLE 17 Hot Plate Assay in mice

A. Subjects

For this test, CD #1 male mice (Charles River) weighing between 20-25grams were used. The mice were weighed, identified, and randomized intogroups of 10.

B. Drug Preparation and Injection Protocol

The mice were usually treated by subcutaneous injection of the compound(or the standard or vehicle) or by oral gavage.

C. Measurement of Analgesic Activity

The mice were evaluated individually for a latency reaction time on thehot plate. The temperature of the hot plate (Sorel, model DS37) was setat 55° C. The mice were observed for signs of discomfort such as lickingor shaking of the paws, attempting to escape (jumping off the plate) ortrembling. The reaction time was recorded when one of these signs wasnoted. The cut off for latency response was 15 seconds so as to preventdamage to the paw tissue. For the determination of analgesic time coursethe mice were observed at different time intervals followingadministration of the compound (or vehicle, or standard). The timeintervals are typically 30, 60 or 120 minutes (or other).

For each time reading, the average reaction time of the control groupwas multiplied by 1.5. The reaction time of each treated animal wascompared to the "control average×1.5". If the reaction time was inferiorto the "control average×1.5", the mouse was considered not to have hadan analgesic effect. If the reaction time was superior to the "controlaverage×1.5" then the mouse was considered to have had an analgesiceffect. If the percentage of mice rendered analgesic was less than 30%,the compound was considered inactive.

FIGS. 1-3 show the antinociceptive effects of compound #9 in mice byevaluating the reaction of the mice in the hot plate test and inhibitionof the writhing response in the PBQ assay.

As shown in FIG. 1, after 15 minutes, the latency response time of themice treated with 2.5 mg/kg of compound #9 is almost maximum. Thereaction time of the mice treated with 5 mg/kg of compound #9 is about19 seconds compared to a control value of approximately 7 seconds. Theseresults indicate that compound #9 does elicit a dose dependent latencyresponse to radiant heat.

FIG. 2 shows the inhibition of the writhing response elicited in mice byoral administration of compound #9 one hour prior to PBQ administration

FIG. 3 demonstrates inhibition of the writhing response elicited in miceby s.c. administration of compound #9, twenty minutes prior to PBQadministration.

In both figures, a dose-dependent inhibition of writhing response wasobserved for of compound #9 both by the oral and sub-cutaneous route.

We claim:
 1. A compound of formula (I): ##STR16## wherein R₁ is H, C₁₋₆alkyl, or C₆₋₁₂ aryl optionally substituted with polar groups;R₂ and R₃are independently H, OH, C₁₋₆ alkyl, --C(NH)--NH₂, a positively chargedgroup, or C₇₋₁₃ aralkyl optionally substituted with NH₂, OH, C₁₋₆ alkyl,or halogen; or R₂ and R₃ together form a 5 to 6 member ring optionallyincorporating a heteroatom; R₄ is H, C₁₋₆ alkyl, OR₆, SR₆ or N(R₆)₂,wherein each R₆ is independently H, C₁₋₃ alkyl; X is S, SO, or SO₂ ; nis an integer from 0 to 2; m is an integer from 1 to
 3. 2. A comundaccording to claim 1, wherein X is selected from S and SO₂, m is 3 and nis
 0. 3. A compound according to claim 2, wherein X is S.
 4. A compoundaccording to claim 3, wherein R₂ is H and R₃ is selected from H, OH and--C(NH)--NH₂.
 5. A compound according to claim 3, wherein R₁ is methyl.6. A compound according to claim 3, wherein R₄ is selected from OH andmethoxy.
 7. A compound according to claim 6, wherein R₄ is OH.
 8. Acompound according to claim 1, selected from:#8b5,6,7,8,9,11,12-heptahydro-3-methoxy-5-methyl-10-thia-5,11-methanobenmocyclodecene-13-amine;#95,6,7,8,9,11,12-heptahydro-3-hydroxy-5-metyl-10-thia-5,11-methanobenzocyclodecen-13-amine(sulphazocine); #10 5,6,7,8,9,11,12-heptahydro-3-hydroxy-5-methyl-10-thia-5,11-methanobenzocyclodecene-13-hydroxylamine; #8a5,6,7,8,9,11,12-hetahydro-3-methoxy-5-methyl-10-thia-5,11-methanobenzocyclo-decen-13-hydroxylamine; #12trans-5,6,7,8,9,11,12-heptahydro-10-sulphono-3-hydroxy-5-methyl-5,11-methanobenzocyclo-decen-13-amine;#9a(-)-trans-5,6,7,8,9,11,12-heptahydro-10-thia-3-hydroxy-5-methyl-5,11-methanobezocyclodecen-13-amine;#9b(+)-trans-5,6,7,8,9,11,12-heptahydro-10-thia-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13amine;and #11trans-5,6,7,8,9,11,12-heptahydro-10-thia-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13-guanidine;#12trans-5,6,7,8,9,11,12-heptahydro-10-sulphono-3-hydroxy-5-methyl-5,11-methanobenzocyclo-decen-13-amine.9. A compound according to claim 1, selected from:#95,6,7,8,9,11,12-heptahydro-3-hydroxy-5-methyl-10-thia-5,11-methanobenzocyclo-decen-13-amine(sulphazocine); and #9a(-)-trans-5,6,7,8,9,11,12-heptahydro-10-thia-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13-amine.10. A method of inducing analgesia in a mammal comprising administeringto said mammal a pharmaceutically effective amount of a compoundaccording to formula (I): ##STR17## wherein R₁ is H, C₁₋₆ alkyl, orC₆₋₁₂ aryl optionally substituted with polar groups;R₂ and R₃ areindependently H, OH, C₁₋₆ alkyl, --C(NH)--NH₂, a positively chargedgroup, or C₇₋₁₃ aralkyl optionally substituted with NH₂, OH, C₁₋₆ alkyl,or halogen; or R₂ and R₃ together form a 5 to 6 member ring optionallyincorporating a heteroatom; R₄ is H, C₁₋₆ alkyl, OR₆, SR₆ or N(R₆)₂,wherein each R₆ is independently H, C₁₋₃ alkyl; X is S, SO, or SO₂ ; nis an integer from 0 to 2; m is an integer from 1 to
 3. 11. The methodaccording to claim 10, wherein X is selected from S and SO₂, m is 3 andn is
 0. 12. The method according to claim 11, wherein, wherein X is S.13. The method according to claim 10, wherein R₂ is H and R₃ is selectedfrom H, OH and --C(NH)--NH₂.
 14. The method according to claim 10,wherein R₁ is methyl and R₄ is OH.
 15. The method according to claim 10,wherein said compound is selected from:#8b5,6,7,8,9,11,12-heptahydro-3-methoxy-5-methyl-10-thia-5,11-methanobenzocyclodecene-13-amine;#95,6,7,8,9,11,12-heptahydro-3-hydroxy-5-methyl-10-thia-5,11-methanobenzocyclodecen-13-amine(sulphazocine); #105,6,7,8,9,11,12-heptahydro-3-hydroxy-5-methyl-10-thia-5,11-methanobenzocyclodecene-13-hydroxylamine;#8a 5,6,7,8,9,11,12-heptahydro-3-methoxy-5-methyl-10-thia-5,11-methanobenzocyclo-decen-13-hydroxylamine; #12trans-5,6,7,8,9,11,12-heptahydro-10-sulphono-3-hydroxy-5-methyl-5,11-methanobenzocyclo-decen-13-amine;#9a(-)-trans-5,6,7,8,9,11,12-heptahydro-10-thia-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13-amine;#9b(+)-trans-5,6,7,8,9,11,12-heptahydro-10-thia-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13-amine;and #11trans-5,6,7,8,9,11,12-heptahydro-10-thia-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13-guanidine;#12trans-5,6,7,8,9,11,12-heptahydro-10-sulphono-3-hydroxy-5-methyl-5,11-methanobenzocyclo-decen-13-amine.16. A method of activating opioid receptors in a mammal comprisingadministering to said mammal an opioid receptor activating amount of acompound according to formula (I): ##STR18## wherein R₁ is H, C₁₋₆alkyl, or C₆₋₁₂ aryl optionally substituted with polar groups;R₂ and R₃are independently H, OH, C₁₋₆ alkyl, --C(NH)--NH₂, a positively chargedgroup, or C₇₋₁₃ aralkyl optionally substituted with NH₂, OH, C₁₋₆ alkyl,or halogen; or R₂ and R₃ together form a 5 to 6 member ring optionallyincorporating a heteroatom; R₄ is H, C₁₋₆ alkyl, OR₆, SR₆ or N(R₆)₂,wherein each R₆ is independently H, C₁₋₃ alkyl; X is S, SO, or SO₂ ; nis an integer from 0 to 2; m is an integer from 1 to
 3. 17. The methodaccording to claim 16, wherein X is selected from S and SO₂, m is 3 andn is
 0. 18. The method according to claim 16, wherein R₂ is H and R₃ isselected from H, OH and --C(NH)--NH₂.
 19. The method according to claim16, wherein R₁ is methyl and R₄ is OH.
 20. The method according to claim16, wherein said compound is selected from:#8b5,6,7,8,9,11,12-heptahydro-3-methoxy-5-methyl-10-thia-5,11-methanobenzocyclodecene-13-amine;#95,6,7,8,9,11,12-heptahydro-3-hydroxy-5-methyl-10-thia-5,11-methanobenzocyclodecen-13-amine(sulphazocine); #105,6,7,8,9,11,12-heptahydro-3-hydroxy-5-methyl-10-thia-5,11-methanobenzocyclodecene-13-hydroxylamine;#8a 5,6,7,8,9,11,12-heptahydro-3-methoxy-5-methyl-10-thia-5,11-methanobenzocyclo-decen-13-hydroxylamine; #12trans-5,6,7,8,9,11,12-heptahydro-10-sulphono-3-hydroxy-5-methyl-5,11-methanobenzacyclo-decen-13-amine;#9a(-)-trans-5,6,7,8,9,11,12-heptahydro-10-thia-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13-amine;#9b(+)-trans-5,6,7,8,9,11,12-heptahydro-10-thia-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13-amine;and#11trans-5,6,7,8,9,11,12-heptahydro-10-thia-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13-guanidine;#12trans-5,6,7,8,9,11,12-heptahydro-10-sulphono-3-hydroxy-5-methyl-5,11-methanobenzocyclo-decen-13-amine.